OVERVIEW: What every practitioner needs to know

Are you sure your patient has tuberculous meningitis? What are the typical findings for this disease?

Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis. It is estimated that 8.8 million new cases of active TB occur worldwide annually (WHO 2011). Though TB primarily affects the lungs, it can affect virtually any organ including the Central Nervous System (CNS) and cause TB meningitis.

TB meningitis should be suspected in all children presenting with meningitis (fever, irritability, neck stiffness, lethargy, headache, vomiting) or neurological symptoms (convulsions, altered mental status, focal neurological deficits) in the setting of recent close contact with a person with infectious TB or other risk factors for developing TB.

What is the typical epidemiology and clinical presentation for TB meningitis?

The value of headache to differentiate TB vs bacterial meningitis is not clear. Cranial nerve palsies, optic atrophy, abnormal extra-pyramidal movements, and focal neurological deficits were reported to be more common with TB vs bacterial meningitis.

Symptom duration of > 5 days has also been used to differentiate TB vs bacterial meningitis. One study found a prodromal stage of 7 days or more, optic atrophy on fundoscopic exam, presence of a focal neurological deficit, and abnormal extra-pyramidal movements to be independent predictors of TB meningitis in children. However, optic atrophy is noted in advanced disease while abnormal extra-pyramidal movements are an uncommon presentation.

Patients with HIV/AIDS are more likely to present with disseminated TB, but their neurological presentation is similar to those without HIV.

Risk factors for acquiring TB:

1. Close contact with an individual with infectious TB (within the past 12 months). Children may be diagnosed as part of a contact investigation (or may be sentinels for a close contact with infectious TB).

2. Born (or spent significant time - months to years) in a country with a high prevalence of TB (most of the world except North America, Western Europe, and Australia).

3. Individuals (or close contacts of individuals) with high risk of TB such as HIV-infected, homeless, users of illicit drugs, those who are incarcerated or migrant farm workers.

In the United States:

1. TB incidence is 3.6 per 100,000 people for a total of 11,181 reported cases (CDC 2010).

Detection of acid-fast bacilli (AFB) and isolation of Mycobacterium tuberculosis from the CSF is diagnostic and should be attempted in all cases. However, AFB microscopy and culture detect bacteria in only one third and half of patients with TB meningitis, respectively. Increasing the volume and number of CSF examinations, and meticulous microscopy (at least 30 min) can increase the sensitivity of both AFB microscopy and culture.

Although nucleic acid amplification tests are highly specific, they are not necessarily more sensitive than culture methods. GeneXpert® MTB/RIF assay (Cepheid) utilizing real-time PCR to detect M. tuberculosis and CSF interferon-gamma release assays may be useful, but large studies are required to determine their accuracy in diagnosing TB meningitis. CSF adenosine deaminase (ADA) activity may also be supportive, but cannot reliably distinguish TB vs bacterial meningitis. Finally, M. tuberculosis antibody detection assays have poor and variable sensitivity and specificity and should not be used.

All efforts to identify M. tuberculosis from sites outside of the central nervous system (CNS) should be made. Chest radiography should be performed in all patients with suspected TB meningitis, because abnormalities suggestive of TB are seen in a third to half of children with TB meningitis. When available, abdominal ultrasound and computed tomography (CT) may also be performed based on clinical judgment. Gastric aspiration (or induced sputum when trained personnel are available) should also be performed in all patients with suspected TB meningitis, as this has been reported to be positive in up to two-thirds of children. Testing additional clinical specimens such as lymph nodes, ascitic fluid, bone marrow, liver, and other sites should be based on clinical judgment.

When available, drug-susceptibility testing should be performed on all positive
M. tuberculosis isolates.

Finally, a positive tuberculin skin test (TST) or peripheral blood interferon-gamma release assays (IGRA) may be useful as supportive evidence. However, neither test can distinguish infection (common in TB endemic countries) from active disease. Additionally, the TST has poor sensitivity (< 50%) and specificity, especially in young, malnourished children in the setting of universal BCG vaccination and non-tuberculous mycobacterial (NTM) infections, which cross-reacts with immune responses. IGRAs are generally more sensitive and specific as they are less affected by prior BCG vaccination and NTM infections than TST and may be useful in diagnosing extrapulmonary disease in malnourished or HIV-infected young children. However, additional studies are needed to validate IGRAs for TB meningitis.

Commercially available blood antibody detection tests are unreliable and have no role in diagnosis.

Would imaging studies be helpful? If so, which ones?

Head CT or magnetic resonance imaging (MRI) should be performed as part of the assessment for TB meningitis.

Imaging studies may be normal in some patients with TB meningitis, although MRI is more sensitive than CT.

Hydrocephalus is observed in 80% of children and is typically less frequently seen in adults or adolescents.

Basal meningeal enhancement is detected in 75%-89% of patients with TB meningitis.

Other findings include tuberculomas (8%-31%) and infarcts (8%-44%). Interestingly, tuberculomas may develop in up to three-fourths of patients during treatment, most of which are asymptomatic.

The combination of hydrocephalus, basal meningeal enhancement, and infarcts was found to be 100% specific for TB meningitis in one study. Similarly, another study demonstrated the presence of a pre-contrast hyperdensity in the basal cisterns to be 100% specific for TB meningitis in children.

Patients with HIV co-infection are reported to have less hydrocephalus and basal meningeal enhancement, but higher frequencies of infarcts and mass lesions.

Confirming the diagnosis

Several clinical algorithms for use in clinical research have been defined for the diagnosis of TB meningitis. A recent consensus case definition based on expert opinion and review of the literature was developed (Marais S et al. Lancet 2010). Although this definition is for use in clinical research and has not been clinically validated, it has been adapted and presented here as a general guide (text below and Table I).

Suspect TB meningitis when one or more of the following are present: fever, irritability, neck stiffness, lethargy, headache, vomiting, convulsions, altered mental status, or focal neurological deficits.

Probable TB meningitis: A total diagnostic score of 10 or more points (when cerebral imaging is not available) or 12 or more points (when cerebral imaging is available) plus exclusion of alternative diagnoses. At least 2 points should come from either CSF or cerebral imaging criteria (Table I).

Possible TB meningitis: A total diagnostic score of 6 to 9 points (when cerebral imaging is not available) or 6 to 11 points (when cerebral imaging is available) plus exclusion of alternative diagnoses (Table I). Possible TB cannot be diagnosed or excluded without doing a lumbar puncture or cerebral imaging.

Not TB meningitis: Alternate diagnosis established.

In practice, most patients presenting with clinical features of TB meningitis will be administered treatments for both TB and bacterial meningitis. Therefore, response to treatment may not reliably distinguish TB vs bacterial meningitis. Moreover, even if only TB treatment is administered, one may not be able to distinguish it reliably from viral meningitis, which usually resolves spontaneously.

No response to treatment may also not preclude the diagnosis of TB meningitis, because patients with multidrug-resistant TB meningitis show little or no clinical improvement with standard TB treatment.

Finally, it should be noted that at least 10% of patients with TB meningitis may develop paradoxical worsening after treatment initiation, which further complicates the use of response to TB treatment as a criterion.

If you are able to confirm that the patient has TB meningitis, what treatment should be initiated?

In practice, most patients presenting with clinical features of TB meningitis will be administered treatments for both TB and bacterial meningitis empirically until a definite diagnosis is established.

Treatment of drug-susceptible TB meningitis involves an intensive phase with four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) for 2 months followed by treatment with two drugs (isoniazid and rifampin) during a prolonged continuation phase (7-10 months), for a total duration of 9-12 months. Data suggest that ethambutol is safe in children, and the World Health Organization (WHO) recommends that children of all ages can be given standard doses of ethambutol. Pyridoxine may be given to avoid the side effects of isoniazid therapy.

The dosages of antituberculosis drugs (first-line) for children are shown below (Table II).

If the patient's isolate is not available, it is generally accepted to guide treatment based on the susceptibility of the organism from the source (close contact).

Expert opinion should be sought for treatment when drug-resistant TB is suspected or confirmed.

It should be noted that at least 10% of patients with TB meningitis may develop paradoxical worsening of their symptoms several weeks to months after initiation of TB treatment. This does not represent treatment failure. The addition of corticosteroids is likely to be beneficial based upon the hypothesized pathogenesis, and the published literature does not contradict this hypothesis.

What are the adverse effects associated with each treatment option?

Isoniazid (INH): The most well known of these is hepatic toxicity, although this is less frequent in children. Patients may develop asymptomatic elevation of liver enzymes or signs / symptoms that resemble viral hepatitis. Elevated liver enzymes may resolve, even with continued therapy. Peripheral neuropathy can occur with INH, presenting with paresthesias that start in the feet and climb to the hands and arms. This phenomenon is dose dependent and is seen in 0.2%-1.2% of patients. It typically appears at around six months of treatment; however, it can appear earlier at higher doses. Risks for neuropathy include increasing age, slow acetylator status, malnutrition, diabetes, renal failure, alcoholism, pregnancy, and breastfeeding. Symptoms are reversible with withdrawal of medication, and pyridoxine supplementation with INH can prevent occurrence. Other side effects include hypersensitivity reactions, morbilliform eruptions, and non-thrombocytopenia purpura.

Rifampin: Studies of rifampin alone for latent tuberculosis in various populations have shown adverse event rates of 22%-26%, resulting in discontinuation of therapy in 1%-14% of cases. These include hepatic, dermatologic, immunologic, hematologic, and gastrointestinal effects. Rifampin turns most bodily fluids orange and can stain contact lenses and clothes. This should be explained to all patients before staring rifampin. Hepatitis is a well described side effect. In addition, rifampin increases the hepatic metabolism of several drugs including oral anticoagulants and oral contraceptive pills. Cutaneous reactions occur in 5%-10% of patients with flushing of the face and neck, with or without pruritis or rash. There have been few reports of generalized hypersensitivity reactions with rash, fever, lymphadenopathy, hepatosplenomegaly, and elevated transaminases. The 'flu-like syndrome' generally occurs with intermittent dosing of rifampin, in patients with poor adherence to daily rifampin therapy, and when daily rifampin is resumed after a drug-free period. Thrombocytopenia is the most common hematologic adverse effect associated with rifampin and may occur in up to 1% of patients.

Pyrazinamide: Pyrazinamide is typically well tolerated in children. As many as 90% of children will develop elevations in uric acid with the drug, but in only 10% of cases will this elevation exceed normal range. Elevated transaminases have been reported in almost 20% of children. Other potential side effects include nausea (1%-5%), fever (0.6%), sideroblastic anemia, lupus, photodermatitis, aseptic meningitis, and leukopenia.

Ethambutol: The main adverse effect of ethambutol is ocular toxicity - a noninflammatory process affecting the central fibers of the optic nerve, causing decreased visual acuity and loss of green vision. These reactions are dose dependent and reversible. However, ocular toxicity in children receiving ethambutol at standard doses is rare. The WHO recommends that children of all ages can be given ethambutol in daily doses of 20 mg/kg (range 15–25 mg/kg) and three times weekly intermittent doses of 30 mg/kg body weight without concerns.

Streptomycin: The most common adverse effects of streptomycin are ototoxicity, rash, and nephrotoxicity. Ototoxicity is a dose dependent vestibulocochlear toxicity. One study reported that 4% of patients on this drug experienced vertigo. Sixty percent of patients in another study demonstrated hearing loss when followed by audiograms, although the finding was of uncertain clinical significance.

What are the possible outcomes of tuberculous meningitis?

Outcomes of this disease, both in the forms of mortality and sequelae, are determined by the neurologic stage at which treatment is initiated. Stage one disease (without any neurological deficits) typically has a lower mortality and morbidity, if therapy is initiated, whereas stage three disease can carry a 50% mortality rate. In studies among adult patients, time between first symptoms and diagnosis ranged significantly, from 2-365 days. However, almost 60% of these patients did receive their diagnosis in less than three weeks. Therapy was started within the first 10 days in 94% of patients. Despite this, median hospitalization time for this cohort was 32 days. Just over half (56%) had complete recovery at 6 months, while 17% died during the hospitalization. Most mortality occurred within the first ten days.

At the time of discharge, 28% of patients had neurologic deficits. At the end of 6 months of follow-up, 13% continued to have neurological sequelae. Cranial nerve palsy, hemiplegia, and paraparesis were the most frequent neurological deficits. Eleven patients developed hydrocephalus requiring neurosurgical intervention. In 8 of these 11, hydrocephalus disappeared within 4 months. Younger age, cranial nerve palsy, and tuberculomas were associated with increased risk of neurological sequelae. Hearing loss in tuberculous meningitis has been reported in several case reports; however, it does not appear to be as common as found with other types of bacterial meningitis.

What causes this disease and how frequent is it?

Tuberculosis initially enters the lungs by inhalation. At this point, macrophages become colonized with tuberculosis. Bacteria can then disseminate to lymph nodes and throughout the systemic circulation. Such extensive bacteremia increases the likelihood that a focus of disease will be established in the CNS.

The central nervous system is protected from the systemic circulatory system by the blood brain barrier. Despite this barrier, a number of pathogens are capable of causing disease, including tuberculosis.

Arnold Rich and Howard McCordock demonstrated with autopsy studies that most TB meningitis patients had a caseating focus in brain parenchyma or meninges, and hypothesized that these foci develop around bacteria during the initial systemic dissemination. Later, these foci may rupture, causing inflammatory meningitis. This phenomenon can cause vascular occlusion and cerebral ischemia. In addition, patients may develop a communicating hydrocephalus because of the obstruction of basal cisterns.

Patients may also develop intracranial tuberculomas, or tuberculous abscesses. Tuberculomas are granulomatous masses of small tubercles consisting of a central core of epithelioid cells surrounded by lymphocytes. Necrotic areas inside these masses contain caseous material with tuberculosis bacilli. If the caseous core of a tuberculoma liquefies, an abscess will result.

Globally, tuberculosis in all of its manifestations is quite common (8.8 million new cases annually). It has re-emerged in industrialized countries due to increased travel, infection with HIV, and the development of multi-drug resistant tuberculosis. Approximately 5%-15% of cases of extrapulmonary tuberculosis will be neurologic, with increased predominance in children and HIV patients.

How do these pathogens/genes/exposures cause the disease?

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Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

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Are additional laboratory studies available; even some that are not widely available?

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How can TB meningitis be prevented?

Prevention of tuberculosis, and thereby prevention of TB meningitis, remains a major public health concern both in the United States and worldwide. Major interventions include early diagnosis of active TB patients to limit the spread of TB.

It is estimated that one third of the world population—or about 2.2 billion people—have latent TB infection. Immunocompetent persons with latent TB have a lifetime risk of 10% of developing reactivated TB disease, while this risk is increased to 5%-10% per year for those infected with HIV. Therefore, identifying people with latent TB infection and providing chemoprophylaxis is a major public health intervention that could prevent TB. In countries with a low incidence of TB, chemoprophylaxis is recommended for all people with untreated latent TB infection. Very recently, the WHO also recommended that TB chemoprophylaxis should also be offered to all HIV-infected individuals with latent TB infection in resource-constrained settings.

Live attenuated BCG, developed in 1908, is the only vaccine licensed to prevent TB. Its efficacy has been inconsistent, with efficacy against pulmonary TB ranging from 0%-80%. However, BCG does protect against disseminated TB and TB meningitis in infancy. Therefore, the WHO currently recommends administering the BCG vaccine intradermally after birth to all infants in areas where TB is endemic.

What is the evidence?

(This reference describes and attempts to standardize a clinical definition for a tuberculous diagnosis, to be used in research. Several committees met to establish this definition, assessing clinical, microbiologic, and radiographic standards. While intended for research, the definition provides important criteria for clinical diagnosis in that it focuses fully on this diagnosis in pediatrics.)

(This study assessed bacterial and host factors that may predispose patients to tuberculous meningitis. It was a high quality case control study, in which cases were patients with TB meningitis (N= 187) and controls were patients with pulmonary tuberculosis (N=237). This study found a significant association between the European-American lineage of tuberculosis and pulmonary infection, with several host alleles associated with TB meningitis. This study is of limited clinical relevance, and was performed in adults. It is unclear if findings will remain the same in children.)

(This study assessed clinical characteristics of tuberculosis, using a case series described over 20 years. Sample size was 837 confirmed cases of TB meningitis, in patients ranging in age from 5 months to 55 years. This study is extremely relevant to children, as 68% of patients described were less than 21 years of age, with 35% of the total sample size less than five years of age.)

(This study compares clinical features of TB meningitis with bacterial meningitis, with a large sample size in both groups (134 and 709, respectively. The study is of high quality, due to its large sample size and use of adequate controls. Patients ranged in age from 5 months to 56 years, with TB meningitis patients having a mean age of 23 years. It is unclear how many patients were children, somewhat limiting the utility of this study in the pediatric population.)

(In this study conducted in Argentina, patients with HIV and patients without HIV, with tuberculous meningitis were compared with respect to CSF findings and drug susceptibility profiles. All patients were older than 15 years of age, limiting generalizability of the study to pediatrics. In addition, HIV-infected patients in this study were severely immunocompromised, limiting generalizability, and drug susceptibility patterns were not similar to that found in other in-country institutions. While this is a well conducted study, it is unclear how generalizable the results are.)

(This is a high quality study of tuberculosis diagnosis in children. It is a prospective cohort study, examining children under the age of 14, comparing ELISpot and TST. The study found an increased sensitivity of TST. This study is extremely relevant to TB diagnosis in pediatrics.)

(Curless et al. describe 4 case reports of children with tuberculous meningitis, describing presentation, radiographic and clinical findings, management and outcome. The strengths of this article are that it concerns children. However, it is a case series and should be discussed in conjunction with more rigorous studies.)

(In this case series of TB meningitis, clinical presentation and outcomes are reviewed in 58 cases. Cases were primarily in adults, limiting generalizability to pediatrics. In addition, this is a case series and should be interpreted in conjunction with case control or cohort studies available.)

(This study assessed the frequency and epidemiology of pulmonary and extrapulmonary tuberculosis in the United States over 13 years. The study is limited by the fact that it was in the US, and may be of limited utility to countries with the highest TB burden in the developing world. Patients in the study had a mean age of greater than 40 years. While children were included in the study, they were of small number, again limiting generalizability to this population. However, the strength in this study lies in its sample size, with greater than 230,000 patients classified.)

(This was a retrospective review of 130 children with confirmed or probable TB meningitis. The study assessed the radiographic findings and distribution of brain infarction, with correlation with outcome. This study is relevant in that it pertains to pediatrics, and examines outcome. However, it is limited in scope, pertaining only to children with cerebral infarction.)

(This study examined sensitivity and specificity of radiographic findings for diagnosis of TB meningitis in children. It pertains to our patient population, and compares findings in TB meningitis to other bacterial meningitis. Another strength of the study is that it uses definite cases of TB meningitis, culture confirmed.)

(This study examined a large group of children, comparing clinical findings of TB meningitis to other bacterial meningitis. The study attempted to define a clinical model for distinguishing TB meningitis from other bacterial meningitis. While the authors found 5 variables that were significantly associated with a TB meningitis diagnosis, they agree that laboratory findings are essential to corroborate this diagnosis, as the consequences of missing the diagnosis are dire. Therefore, although helpful in delineating clinical characteristics, caution should be used when interpreting this rule.)

(This is a case report of a 17-year-old with tuberculous meningitis and tuberculomas with paradoxical worsening of symptoms after initiation of TB therapy. The accompanying literature review is exhaustive and includes adult and pediatric patients, assessing management and clinical outcomes.)

(This is an extensive literature review describing side effects of antiTB therapy, and providing expert opinion as to its use. There is a wealth of experience in this paper, and it provides the standard of care for TB management.)

(This is again an extensive literature review describing adverse effects to antiTB medications. It again comprises expert opinion. While not specific for children, it provides general guidance in the utilization and monitoring of these drugs.)

(This extensive review examined the pathogenesis of TB meningitis, with relevance to both adults and children. It provides extensive description as to how TB meningitis occurs, with potential steps for intervening.)

Ongoing controversies regarding etiology, diagnosis, treatment

-Duration of steroids: Some studies have advocated a longer duration of steroids (i.e., 6-9 months), although the consensus appears to be a six-week taper described above.

-Management of chronic cases of tuberculosis (failed initial treatment), particularly in resource poor settings: General consensus appears to be an individualized treatment plan based on susceptibility data. However, this is not often feasible in resource-limited settings.

-According to a recent Cochrane review, the use of adjunctive corticosteroids in patients with HIV and TB meningitis is inconclusive.